Neuropathic pain, refers to a pain that occurs after nerve injury or a disease of the somatosensory system, is a debilitating chronic clinical condition, one hallmark symptom of which is tactile hypersensitivity to pain. Although acute pain (duration <3 months) can be efficiently controlled by a large arsenal of various drugs, such as non-steroid anti-inflammatory drugs (NSAIDs) or opioids for severe cases, the current treatment of chronic pain (duration >3 months), especially neuropathic pain, is essentially symptomatic and unsatisfactory for most patients. Indeed, a number of pain medications are available on the pharmaceutical market, most of which have been initially marketed for other indications, e.g. epilepsy and depression. These medications are however only partially efficacious against neuropathic pain: only a limited number of patients achieve a 50% reduction of their pain symptoms and it is still today unfortunately observed that some neuropathic pain syndromes are completely refractory to these medications, thus affecting considerably the quality of life of these patients (Finnerup et al., Lancet Neurol. 2015, 14:162-173). Moreover, the existing medications often generate a large variety of adverse effects that limit their use in patients: they can elicit dizziness, somnolence, tiredness, constipation, dry mouth, nausea, vomiting, and weight gain.
FLT3 is a member of the class III receptor tyrosine kinase (RTK) family which comprises stem cell factor (SCF) receptor (c-kit), colony-stimulating factor type-I (CSF-1) receptor (c-fms) and platelet-derived growth factor (PDGF) receptor (PDGFR). FLT3, like other RTKs, is a transmembrane receptor, which contains an extracellular domain interacting with its ligand FL, and an intracellular domain containing a kinase domain responsible of auto-phosphorylation. Upon activation, FLT3 dimerizes and auto-phosphorylates tyrosine residues present in its intracellular domain. FLT3 is predominantly expressed in the human lympho-hematopoietic system, which generates blood cells. FL/FLT3 signaling regulates proliferation, survival and differentiation of hematopoietic/progenitor cells and can lead to the differentiation of progenitors into dendritic cells. Mutations in FLT3 responsible for auto-activation have been identified in up to 30% of acute myeloid leukemia (AML) patients, worsening the prognostic.
Indeed, FLT3 receptor inhibitors were initially known for their use in the treatment of cancer. Small molecule kinase inhibitors (Receptor Tyrosine Kinase Inhibitors; RTKI) are recognized drugs that have been intended to treat human patients with various cancers, some of them being already marketed for oncology indications, in AML and other malignant diseases in which FLT3 activation is implicated. These compounds act via blocking the intracellular kinase domain of the receptor tyrosine. They inhibit FLT3 in cellular assays and are also efficacious in mouse models of these cancerous pathologies. In phase 1 and phase 2 clinical trials, conducted primarily in relapsed or refractory AML patients, clinical responses were consistently observed with these drugs.
In contrast to FLT3, FL is expressed in most human tissues and in blood. FLT3 expression has been also identified in the nervous system (Rosney et al. Oncogene; 1991, 6, 1641-1650). The only known role of FL/FLT3 interactions on neuron functioning on the somato-sensory system is the developmental regulation of neural stem cells proliferation and a synergistic effect with nerve growth factor (NGF) promoting early embryonic DRG sensory neuron survival in vitro.
Moreover, it is known from document WO2011/083124 to use a FLT3 receptor inhibitor for the treatment of pain disorders. Neuropathic pain is cited among a large list of pain disorders that encompasses acute pain, chronic pain, neuropathic pain, inflammatory pain, low back pain, post-operative pain, cancer pain, vascular headache such as migraine, fibromyalgia, hyperalgesia such as mechanical ant thermal hyperalgesia, allodynia such as thermal and mechanical allodynia, peripheral sensitization of pain mechanisms and central sensitization of pain mechanisms.
However, said document is silent on which specific pain disorders that can be treated with an FLT3 receptor inhibitor and on specific daily dosages of said FLT3 receptor inhibitor aiming at specifically dealing with a particular pain disorder. WO2011/083124 discloses the possibility of dosages of an FLT3 receptor inhibitor for treating a pain disorder in the range of 0.1 to 50 mg, which is a range too large to be adapted to a particular pain disorder and to avoid side-effects, particularly on long-term use needed for chronic pain.
Indeed, at doses used for the treatment of different cancer diseases, FLT3 receptor inhibitors generate numerous and often serious (grade 3, 4) adverse events. These include frequent adverse reactions such as fatigue, asthenia, fever, diarrhea, nausea, mucositis/stomatitis, vomiting, dyspepsia, abdominal pain, constipation, hypertension, peripheral edema, rash, skin disorders. Potentially serious adverse reactions such as hepatotoxicity, left ventricular dysfunction, congestive heart failure, QT interval prolongation, hemorrhage, hypertension, thyroid dysfunction, pancreatitis, and adrenal function have also been observed (Terada et al., Pharmacology & Therapeutics, 2015, 152: 125-134; Gathalia et al., Critical Rev in Oncol/Hematol, 2015, 93:257-276; ibid, Critical Rev in Oncol/Hematol, 2015, 94: 136-145; ibid, Critical Rev in Oncol/Hematol, 2015, 94: 228-237; ibid, British Journal of Cancer, 2015, 112:296-305; Youjin et al., Lancet Oncol 2009; 10: 967-74; Massey et al., Support Care Cancer, 2015, 23:1827-1835; Santoni et al., Int J Cancer. 2014, 135:763-773).
In particular, there is a continuing need for providing the skilled person with means for treating patients suffering from neuropathic pain and chronic pain comprising a neuropathic component, for which limited treatments are currently available as reminded above, and at low daily dosage for long-term treatment, in particular with sufficient efficiency and for avoiding the occurrence of aforementioned adverse effects.
Because different pain disorders may proceed from distinct mechanisms, there is an additional need to provide the skilled person with efficient drugs for treating patients suffering from neuropathic pain and chronic pain comprising a neuropathic component addressing the cause and not only the consequences of the disease in adapted daily dosages, in particular minimum daily dosages, for avoiding the occurrence of adverse effects as reminded above.
The present invention has for purpose to meet these needs.